The invention relates to an active substance-containing plaster for the controlled administration of active substances to the skin, which has a back and a skin side, with a back layer, an active substance reservoir subdivided substantially perpendicularly to the skin contact surface of the plaster and having one or more active substances, an adhesive device on the skin side and optionally a cover layer detachable prior to the application of the plaster, it being possible to reduce the size of the active substance release surface of the plaster by a predetermined amount by removing part of the active substance reservoir, as well as the use thereof and a process for the controlled administration of active substances to the skin.
The invention more particularly relates to those plasters used as transdermal therapeutic systems for the controlled administration of medical active substances or also cosmetically active substances to the human or animal skin. A therapeutic system is a medicament or active substance-containing means or administration form, which delivers one or more active substances in a continuous manner, at a predetermined rate and over a given time interval to a predetermined application point. These systems are therapeutic precision instruments, whose construction requires extraordinary measures in order to ensure continuous active substance release.
Plaster-like therapeutic systems have already been developed for the most varied uses and, apart from a topical effect, a systemic effect can also be obtained. The multiplicity of active substances applicable in this way and their different chemical, physical and pharmacological characteristics make it impossible to cover all therapeutic problems with a single system.
Numerous therapeutic systems for the administration of medical active substances to the skin are known, a summary being e.g. provided in Klaus Heilmann "Therapeutische Systeme" Ferdinand Enke Verlag, Stuttgart, 1977. The prior art systems were not able to provide a completely satisfactory action in all cases.
In the conventional structure of a transdermal plaster-like therapeutic system there is an active substance reservoir, which contains the active substance in solid, liquid or dissolved form and a pressure-sensitive adhesion layer (contact adhesive), through which the system is closely liked with the skin. It is important that a whole-area contact is ensured between the active substance release surfaces to the skin throughout the application of the systems, in order to make sure of the active substance release kinetics. This can be achieved not only through an uninterrupted adhesion layer, but also by restricted adhesion areas in the skin contact layer of the plaster.
Although the hitherto known plaster-like therapeutic systems permit a uniform or continuously decreasing application of an active substance over a predetermined time, they do not permit specific active substance release kinetics, such as a planned reduction of the active substance release after a predetermined time, or a graduated active substance release quantity per unit of time.
This measure is e.g. necessary if the active substance dose has to be reduced in a planned manner during the application period for therapeutic reasons. The same problem arises if, during the application of a combination product, the release of one active substance in the combination must be terminated after a predetermined time. In such cases, it is in principle possible to solve the problem by using two transdermal plasters, whereof one is removed at the given time. However, this leads to problems for patients, particularly if they are aged. Therefore it is easy to forget to apply the second plaster. In a combination of two plasters with different active substance release surfaces, there is also a risk of choosing the incorrect combination (two identical plasters), or the removal of the wrong plaster. The same complications occur if plasters with different active substances have to be combined and there is in this case also the problem of double storage. Thus, the use of two plasters leads to numerous disadvantages and the avoidance thereof forms an objective of the invention.
The proposal of combining two plasters, whereby part thereof can be detached with the aid of a predetermined breaking line, admittedly improves compliance, but leads to handling problems. Thus, the part to be detached can only be handled by raising from the skin and in undesired manner at least a part of the plaster still remaining on the skin is raised and must be firmly held during detachment. Thus, pressure is exerted on the sensitive transdermal system, which can negatively influence the active substance release rate.
U.S. Pat. No. 4,297,995 describes a manipulatable active substance plaster, in which the active substance reservoir is subdivided, but is integrated into a single plaster. The active substance reservoir parts are arranged in concentric rings about a disk-like central portion. The overall construction of the plaster with a mechanical fixing of the reservoir to the back layer only makes it possible to change the active substance release surface prior to the application of the plaster, i.e. prior to plaster application the doctor/patient can choose which dose is to be administered, but for changing the active substance release during plaster application, the plaster must be detached from the skin, while interrupting therapy and this can also lead to damage and contamination to the plaster support surface. As yet no satisfactory solution has been found for the associated problems of repositioning and the permanent refixing of the system to the skin.
Therefore the problem of the present invention is to provide an improved therapeutic transdermal system, which makes it possible to realize more complicated changes to the active substance release than have hitherto been possible.
This problem is solved by a plaster of the aforementioned type, which is characterized in that at least part of the active substance reservoir can be detached, while leaving one or more parts of said reservoir on the skin and the part of the active substance reservoir left behind on the skin has a better adhesion to the skin than to the back layer.
The present invention provides a transdermal drug delivery system that allows the user to easily and effectively remove part of the system, while leaving the remaining part intact and undisturbed. Such is of extreme utility in step-wise administration of drugs, such as nicotine, as well as other drugs, where the dosage must be changed as "plasters" are successfully applied over time. The system has at least two drug reservoirs, a first and second reservoir. The second reservoir is removed and the first remains attached to the akin. This is accomplished by the use of a peel-off layer which covers the back of the first reservoir, which is made of an essentially non-sticky material. A back layer, which covers and encloses the entire patch rests on top of the peel-off layer and the peel-off layer adheres to the first reservoir. When the back layer is removed, the second reservoir is lifted off the skin, but since the peel-off layer does not adhere to the back layer, the first reservoir remains and adheres to the skin. This allows the user to remove the desired reservoir with one hand and in-one motion.
Due to the fact that, according to the invention, the active substance reservoir is partly detachable whereby the part of the active substance reservoir which is not to be detached has a greater adhesion to the skin than to the back layer, after removing a predetermined plaster part with the active substance reservoir part adhering thereto, there is left behind a predetermined active substance reservoir part on the skin, which can e.g. be alone removed following the desired application period. Advantageously the active substance reservoir of the inventive plaster is in two parts.
In the case of given therapies with varying or marked concentration-fluctuating active substance administrations, it can also be advantageous for the active substance reservoir to be in three parts. The active substance release surfaces of the active substance reservoir parts can be geometrically identical or different. The active substance release surfaces can be juxtaposed, or one active substance reservoir part can completely surround one or more other active substance reservoir parts, considered in a flat or surface-based manner. The subdivision of the partial surfaces is dependent on the therapeutic requirements. Thus, e.g. one active substance reservoir part can circularly surround one or more other active substance reservoir parts.
The release surface--size ratio of one active substance reservoir part to another is preferably in the range between approximately 1:1 and 1:10. The same active substance or the same active substance combination can be present in all the active substance reservoir parts.
Particularly preferred products are plasters with the following active substances, but it is also possible to process random other transdermally administrable active substance combinations known to the medical Expert: asthma/bronchodilators, such as e.g. clenbuterol, proctaterol and salbutamol and vasodilators, such as e.g. bencyclane and cinnarizine, compounds to cause people to stop smoking, e.g., nicotine and lobeline.
Thus, with the aid of the inventive plaster, in such cases it is possible to reduce the administration dose in a planned and controlled manner during application.
However, the active substance reservoir parts can also contain different active substances or different active substance combinations, so that during application it is possible to interrupt or stop one active substance or active substance combination. Examples for different active substances in the active substance reservoir parts are: oestrogen/gestagen (contraceptives), dexamethasone/prednisolone (in the case of inflammatory, rheumatic muscle and joint diseases), nitro-glycerin/.beta.-blockers (for cardiac diseases), phenytoin/phenobarbital/caffeine (for epilepsy) and amitriptyline/chlordiazepoxide (psychopharmaceuticals).
All suitable active substances belong to the groups having either a topical or systemic action. In at least one active substance reservoir part there can be different active substance/active substance combinations as compared with the other active substance reservoir part or parts.
The preferred use of the inventive plasters is in local and systemic, transdermal active substance administration in human or animal medicine or in cosmetics.